Our laboratory has discovered a broad, new class of catalytic processes that promote C-C bond formation via direct alcohol C-H functionalization. In the prior funding period, this technology enabled total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, availing the most concise routes to any member of these respective natural products families. In the proposed funding period, these routes will be adapted to prepare functional analogues of bryostatin and trienomycin. Our bryostatin analogues will be evaluated in an ongoing collaboration with Dr. Peter M. Blumberg, who is Chief, Molecular Mechanisms of Tumor Promotion Section in the Laboratory of Cancer Biology and Genetics at the NCI. The bryostatin analogues also will be evaluated in HIV viral reactivation assays in collaboration with colleagues at GlaxoSmithKline. Trienomycin analogues will be evaluated at the Texas Institute for Drug and Diagnostics Development (TI-3D). Having utilized alcohol C-C coupling to streamline the synthesis of several type I polyketides, we will now begin to evolve a suite of methods to assemble therapeutically relevant type II polyketide natural products, such as (+)-lactonamycin, which displays potent antibacterial activity against MRSA. TYPE I Polyketides Prepared in the Prior Funding Period Me Me Me O HO OAc MeO2C Me OO Me Me OH OH O Me Me OH O OH O O Me Me O OH O Me OH Me Me O CO2Me 6-DEOXYERYTHRONOLIDE B BRYOSTATIN 7 14 Steps (LLS), 3 C-C Bonds Formed 20 Steps (LLS), 5 C-C Bonds Formed via Hydrogen Mediated C-C Coupling via Hydrogen Mediated C-C Coupling 26 Steps (Masamune), 23 Steps (Evans) 41 Steps (Masamune), 43 Steps (Yamamura) 42 Steps (Danishefsky), 23 Steps (White) 42 Steps (Evans), 30 Steps (Keck) 28 Steps (Trost), 25 Steps (Wender) Me OH OH OH OH OH Me Me OH O Me HO O Me (+)-ROXATICIN 20 Steps (LLS), 8 C-C Bonds Formed via Hydrogen Mediated C-C Coupling 45 Steps (Mori), 31 Steps (Rychnovsky) 29 Steps (Evans) HO The ideal synthesis creates a O O Me complex skeleton... in a sequence Me Me OMe NH only of successive construction MeO O O O OMe Me reactions involving no intermediary HO O refunctionalizations, and leading directly to the structure of the MeO O O O OMe O OMe target, not only its skeleton but OMe Me Me H also its correctly placed O O O N O functionality. Me R Me CYANOLIDE A TRIENOMYCINS A and F Hendrickson, J. B. 6 Steps (LLS), 2 C-C Bonds Formed 16 Steps (LLS), 3 C-C Bonds Formed J. Am. Chem. Soc. via Hydrogen Mediated C-C Coupling via Hydrogen Mediated C-C Coupling 1975, 97, 5784. 14 Steps (Hong), 17 Steps (Reddy) 30 Steps (Smith), 24 Steps (Panek) 14 Steps (She), 17 Steps (Pabbaraja) 35 Steps (Hayashi) 12 Steps (Rychnovsky), 15 Steps (Jennings) TYPE II Polyketides Inspire the Development of Convergent Methods for their Assembly; Functional Bryostatin Analogues Me Me O O OAc MeN OH O O OO O OMe O OH O HO O O Me Me OH OO O O Me OH Me OH OMe C7H15 O (+)-Lactonamycin O Potent activity against vancomycin-resistant Enterococcus (VRE) and methicillin-resistant seco-B-ring Analogue WN-1 Staphylococcus aureus (MRSA) Ki = 16.1 nM, PKC A- and C rings common to analogues that display bryostatin 1-like behavior in U937 histiocytic lymphoma cells, yet PMA-like response is observed. Inhibits the growth of multiple leukemia cell lines Made via H2-mediated C-C coupling in 17 Steps (LLS)